Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients

Abstract

IntroductionAngiotensin-converting enzyme (ACE) and ACE2 have been implicated in the regulation of vascular physiology. Elevated synovial and decreased or normal ACE or ACE2 levels have been found in rheumatoid arthritis (RA). Very little is known about the effects of tumor necrosis factor α (TNF-α) inhibition on ACE or ACE2 homeostasis. In this study, we assessed the effects of one-year anti-TNF therapy on ACE and ACE2 production in RA and ankylosing spondylitis (AS) in association with other biomarkers.Patients and MethodsForty patients including 24 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 16 AS patients treated with ETN were included in a 12-month follow-up study. Serum ACE levels were determined by commercial ELISA, while serum ACE2 activity was assessed using a specific quenched fluorescent substrate. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. In addition, CRP, rheumatoid factor (RF) and ACPA were also measured. All assessments were performed at baseline and 6 and 12 months after treatment initiation.ResultsAnti-TNF therapy increased ACE levels in the full cohort, as well as in the RA and AS subsets. ACE2 activity increased in the full cohort, while the ACE/ACE2 ratio increased in the full cohort and in the RA subset (p < 0.05). Uni- and multivariable regression analyses determined associations between ACE or ACE/ACE2 ratios at different time points and disease duration, CRP, RF, FMD and IMT (p < 0.05). ACE2 activity correlated with CRP. The changes of ACE or ACE2 over 12 months were determined by treatment together with either RF or FMD (p < 0.05).ConclusionsAnti-TNF treatment may increase ACE and ACE2 in the sera of RA and AS patients. ACE and ACE2 may be associated with disease duration, markers of inflammation and vascular pathophysiology. The effects of TNF inhibition on ACE and ACE2 may reflect, in part, the effects of these biologics on the cardiovascular system.

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“…Coagulation screening tests (prothrombin time, activated partial thromboplastin time, thrombin time) and fibrinogen were measured by routine methods (Siemens Healthcare Diagnostic Products, Marburg, Germany). ACE and ACE2 activities were assessed using specific quenched fluorescent substrates as described earlier ( 5 , 6 ). Anti-SARS-CoV-2 rapid antigen test was carried out in the patient and controls from nasopharyngeal swab samples (Genedia, St. Ingbert, Germany).…”

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“…Fibrinogen levels were measured according to the method of Clauss on a BCS coagulometer (Siemens Healthcare Diagnostic Products, Marburg, Germany). Serum angiotensin convertase enzyme 2 (ACE2) activity was assessed using a specific quenched fluorescent substrate as described earlier ( 17 ). For the execution of thrombin generation assay, aliquots of citrated plasma were stored at −80°C until analysis.…”

Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis

“…Serum ACE levels were determined by a commercial human ACE ELISA (R&D Systems) as described previously ( 15 , 29 ). ELISA plates (Greiner Bio-One) were coated with 80 ng/well capture antibody.…”

“…Recently, we found that anti-TNF agents increased ACE and ACE2 levels, as well as the ACE/ACE2 ratio in RA patients. We correlated ACE and ACE2 levels with disease duration, C-reactive protein (CRP), rheumatoid factor (RF), FMD and ccIMT ( 29 ).…”